Adavosertib and Local Radiation Therapy in Treating Children With Newly Diagnosed Diffuse Intrinsic Pontine Gliomas

NCT ID: NCT01922076

Last Updated: 2024-01-31

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 46 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-09-03
• Study Completion Date: 2022-09-30

Brief Summary

This phase I trial studies the side effects and the best dose of adavosertib when given together with local radiation therapy in treating children with newly diagnosed diffuse intrinsic pontine gliomas. Adavosertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays, gamma rays, neutrons, protons, or other sources to kill tumor cells and shrink tumors. Giving adavosertib with local radiation therapy may work better than local radiation therapy alone in treating diffuse intrinsic pontine gliomas.

Detailed Description

PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) or recommended phase 2 dose and schedule of the adavosertib (Wee1 inhibitor AZD1775 [MK-1775]) administered concurrently with radiation therapy in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG).

II. To define and describe the toxicities of AZD1775 (MK-1775) given concurrently with radiation therapy in children with newly diagnosed DIPG.

III. To characterize the pharmacokinetics of AZD1775 (MK-1775) in children with newly diagnosed DIPG when given concurrently with radiation therapy.

SECONDARY OBJECTIVES:

I. To preliminarily define the antitumor activity of AZD1775 (MK-1775) within the confines of a phase 1 study, including response rate, progression free survival, and overall survival of treated patients.

II. To assess the biologic activity of AZD1775 (MK-1775) by measuring expression of phosphorylated-cell division cycle 2 G1 to S and G2 to M (p-CDC2) (cyclin-dependent kinase 1 [CDK1]) and phosphorylated-histone H3 (p-HH3) in peripheral blood mononuclear cells (PBMCs) before and after administration of AZD1775 (MK-1775) in children with newly diagnosed DIPG.

III. To assess the biologic activity of AZD1775 (MK-1775) by measuring expression of gamma-H2A histone family, member X (H2AX) in PBMCs, a marker of deoxyribonucleic acid (DNA) double-strand breaks (dsDNA), before and after administration of AZD1775 (MK-1775) in children with newly diagnosed DIPG.

OUTLINE: This is a dose-escalation study of adavosertib.

Patients undergo radiation therapy 5 days a week for 6 weeks (up to 30 fractions). Patients also receive adavosertib orally (PO) on days 1-5 of weeks 1, 3, and 5; days 1-5 of weeks 1, 3, and 5 AND days 1, 3, and 5 of weeks 2, 4, and 6; OR days 1-5 of weeks 1-6 depending on dose level assignment. Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, every 2 months for 6 months, and then every 3 months thereafter.

Conditions

Anaplastic Astrocytoma; Anaplastic Oligoastrocytoma; Diffuse Intrinsic Pontine Glioma; Diffuse Midline Glioma, H3 K27M-Mutant; Glioblastoma; Gliosarcoma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment (adavosertib, radiation therapy)

Patients undergo radiation therapy 5 days a week for 6 weeks (up to 30 fractions). Patients also receive adavosertib PO on days 1-5 of weeks 1, 3, and 5; days 1-5 of weeks 1, 3, and 5 AND days 1, 3, and 5 of weeks 2, 4, and 6; OR days 1-5 of weeks 1-6 depending on dose level assignment. Treatment continues in the absence of disease progression or unacceptable toxicity.

Group Type: EXPERIMENTAL

Adavosertib

Intervention Type: DRUG

Given PO

Laboratory Biomarker Analysis

Intervention Type: OTHER

Correlative studies

Pharmacological Study

Intervention Type: OTHER

Correlative studies

Radiation Therapy

Intervention Type: RADIATION

Undergo radiation therapy

Interventions

Adavosertib

Given PO

Intervention Type: DRUG

Laboratory Biomarker Analysis

Correlative studies

Intervention Type: OTHER

Pharmacological Study

Correlative studies

Intervention Type: OTHER

Radiation Therapy

Undergo radiation therapy

Intervention Type: RADIATION

Other Intervention Names

AZD-1775; AZD1775; MK-1775; MK1775; Cancer Radiotherapy; Energy Type; ENERGY_TYPE; Irradiate; Irradiated; Irradiation; Radiation; Radiation Therapy, NOS; Radiotherapeutics; Radiotherapy; RT; Therapy, Radiation

Eligibility Criteria

Inclusion Criteria

• Patients with newly diagnosed DIPGs, defined as tumors with a pontine epicenter and diffuse involvement of the pons, are eligible without histologic confirmation

• Patients with brainstem tumors that do not meet these criteria or are not considered to be typical intrinsic pontine gliomas will only be eligible if the tumors are biopsied and proven to be an anaplastic astrocytoma, glioblastoma, gliosarcoma, diffuse midline glioma with histone H3 K27M mutation, or anaplastic mixed glioma; patients with pilocytic astrocytoma, fibrillary astrocytoma, gangliogliomas, or other mixed gliomas without anaplasia are not eligible
• Patients with disseminated disease are not eligible, and magnetic resonance imaging (MRI) of spine must be performed if disseminated disease is suspected by the treating physician
• Enrollment must be no later than 28 days after the date of radiographic diagnosis or surgery, whichever is the later date
• Patients must have a body surface area >= 0.35 m^2 at the time of study enrollment
• Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• Patients must not have received any prior anti-cancer therapy such as chemotherapy, radiation therapy, immunotherapy or bone marrow transplant for the treatment of DIPG; prior dexamethasone and/or surgery are allowed
• Peripheral absolute neutrophil count (ANC) >= 1000/mm^3
• Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or
• A serum creatinine based on age/gender as follows:

• 0.8 mg/dL (3 to < 6 years of age)
• 1.0 mg/dL (6 to < 10 years of age)
• 1.2 mg/dL (10 to < 13 years of age)
• 1.5 mg/dL (male) or 1.4 mg/dl (female) (13 to < 16 years of age)
• 1.7 mg/dL (male) or 1.4 mg/dl (female) (>= 16 years of age)
• Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x ULN = 135 units per liter (U/L); for the purpose of this study, the ULN for SGPT is 45 U/L
• Serum glutamic oxaloacetic transaminase (SGOT) aspartate aminotransferase [AST] =< 3 x ULN = 150 U/L; for the purpose of this study, the ULN for SGOT is 50 U/L
• Serum albumin >= 2 g/dL
• Patients with seizure disorder may be enrolled if on non-enzyme inducing anticonvulsants and well controlled
• Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE] version [v]5) resulting from prior therapy must be =< grade 2 with the exception of tendon reflex (deep tendon reflex [DTR]); any grade of DTR is eligible
• Corrected QT interval (QTc) =< 480 msec
• All patients and/or their parents or legally authorized representatives must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines

Exclusion Criteria

• Pregnant or breast-feeding women may not be entered on this study; pregnancy tests must be obtained in girls who are post-menarchal; negative serum or urine pregnancy test within 3 days prior to enrollment
• Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive methods as follows: fertile females of childbearing potential who agree to use adequate contraceptive measures from 2 weeks prior to the study and until 1 month after study treatment discontinuation; male patients willing to abstain or use barrier contraception (i.e. condoms) for the duration of the study and for 3 months after treatment stops
• Patients receiving corticosteroids are eligible for this trial
• Patients who are currently receiving another investigational drug are not eligible
• Patients who are currently receiving other anti-cancer agents are not eligible
• Patients must not currently be receiving enzyme inducing anticonvulsants
• Patients should avoid concomitant medication known or suspected to prolong QTc interval or cause Torsades De Pointes; if possible, alternative agents should be considered; patients who are receiving drugs that prolong the QTc are eligible if the drug is necessary and no alternatives are available
• Patients who are currently receiving drugs that are strong or moderate inhibitors and/or inducers of CYP3A4, sensitive CYP3A4 substrates and CYP3A4 substrates with a narrow therapeutic range are not eligible; the use of aprepitant or fosaprepitant as an antiemetic is prohibited due to early drug interaction data demonstrating increased exposure to AZD1775; the use of hydroxymethylglutary (HMG) coenzyme-A (Co-A) inhibitors such as atorvastatin is prohibited
• Herbal preparations are not allowed throughout the study; these herbal medications include but are not limited to: St. John's wort, kava, ephedra (ma hung), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto and ginseng; patients should stop using these herbal medications 7 days prior to study enrollment
• Any known hypersensitivity or contraindication to the components of the study drug AZD1775
• Patients must not receive metformin for at least 5 days prior to enrollment and for the duration of study treatment
• Patients must be able to swallow capsules; nasogastric or gastrostomy feeding (G) tube administration is not allowed
• Patients who have an uncontrolled infection are not eligible
• Patients who have received a prior solid organ transplantation are not eligible
• Patients with cardiac diseases ongoing or in the past 6 months (e.g. congestive heart failure, acute myocardial infarction, significant uncontrolled arrhythmias) are not eligible for this trial
• Major surgical procedures =< 28 days of beginning study treatment, or minor surgical procedures (including ventriculoperitoneal [VP] shunt placement or stereotactic biopsy of the tumor) =< 7 days; no waiting period required following port-a-cath or other central venous access placement
• Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible

• Minimum Eligible Age: 37 Months
• Maximum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Sabine Mueller

Role: PRINCIPAL_INVESTIGATOR

COG Phase I Consortium

Locations

Children's Hospital of Alabama

Birmingham, Alabama, United States

Children's Hospital Los Angeles

Los Angeles, California, United States

Children's Hospital of Orange County

Orange, California, United States

UCSF Medical Center-Parnassus

San Francisco, California, United States

UCSF Medical Center-Mission Bay

San Francisco, California, United States

Children's Hospital Colorado

Aurora, Colorado, United States

Children's National Medical Center

Washington D.C., District of Columbia, United States

Children's Healthcare of Atlanta - Egleston

Atlanta, Georgia, United States

Lurie Children's Hospital-Chicago

Chicago, Illinois, United States

Riley Hospital for Children

Indianapolis, Indiana, United States

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

C S Mott Children's Hospital

Ann Arbor, Michigan, United States

University of Minnesota/Masonic Cancer Center

Minneapolis, Minnesota, United States

Washington University School of Medicine

St Louis, Missouri, United States

NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center

New York, New York, United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

Oregon Health and Science University

Portland, Oregon, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, United States

Saint Jude Children's Research Hospital

Memphis, Tennessee, United States

Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center

Houston, Texas, United States

Seattle Children's Hospital

Seattle, Washington, United States

Children's Hospital of Wisconsin

Milwaukee, Wisconsin, United States

Hospital for Sick Children

Toronto, Ontario, Canada

Countries

United States; Canada

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

NCI-2013-01602

Identifier Type: REGISTRY

Identifier Source: secondary_id

COG-ADVL1217

Identifier Type: -

Identifier Source: secondary_id

ADVL1217

Identifier Type: OTHER

Identifier Source: secondary_id

ADVL1217

Identifier Type: OTHER

Identifier Source: secondary_id

UM1CA097452

Identifier Type: NIH

Identifier Source: secondary_id

View Link

NCI-2013-01602

Identifier Type: -

Identifier Source: org_study_id